In other species: cattle , dog , horse , red fox , pig , sheep , jaguar , jaguarundi , American black bear , woolly mammoth , domestic cat , rabbit , domestic guinea pig , goat , Arctic fox , rock pocket mouse , oldfield mouse , lesser earless lizard , little striped whiptail , water buffalo , domestic yak , alpaca , , coyote , reindeer , Geoffroy's cat , Colocolo , ass , Arabian camel , Mongolian gerbil , raccoon dog , fallow deer , zebu , lorises , antarctic fur seal

Category: Pigmentation phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 266300 (trait) , 155555 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2009

Cross-species summary: The extension locus encodes the melanocyte-stimulating hormone receptor (MSHR; now known as MC1R). This receptor controls the level of tyrosinase within melanocytes. Tyrosinase is the limiting enzyme involved in synthesis of melanins: high levels of tyrosinase result in the production of eumelanin (dark colour, e.g. brown or black), while low levels result in the production of phaeomelanin (light colour, e.g. red or yellow). When melanocyte-stimulating hormone (MSH) binds to its receptor, the level of tyrosinase is increased, leading to production of eumelanin. The wild-type allele at the extension locus corresponds to a functional MSHR, and hence to dark pigmentation in the presence of MSH. As explained by Schneider et al. (PLoS Genet 10(2): e1004892; 2015), "The most common causes of melanism (black coat) mutations are gain-of-function alterations in MC1R, or loss-of function alterations in ASIP, which encodes Agouti signaling protein, a paracrine signaling molecule that inhibits MC1R signaling". Mutations in MC1R have been associated with white colouring in several species.

History: McRobie et al. (2014) showed that the same 24bp deletion occurs in North American gray squirrels as in British gray squirrels. Noting that the British gray squirrel arose from importations from the North American squirrel in the late 19th century, the authors concluded that "the melanic gray squirrel found in the British Isles originated from one or more introductions of melanic gray squirrels from North America".

Molecular basis: By sequencing an obvious candidate gene in three coat-colour phenotypes (the wild-type gray, a jet-black, and a brown–black phenotype) of the British gray squirrel, McRobie et al. (2009) identified a causal mutation in MC1R: "The gray phenotype was homozygous for the wild-type allele E^+, the jet-black phenotype was homozygous for the MC1R-Δ24 allele E^B ["at amino acid positions 87–94"], and the brown–black phenotype was heterozygous for the E^+ and E^B alleles."

McRobie et al. (2014; FEBS Lett) showed "that agouti signalling protein (ASIP) is an inverse agonist to the MC1R-wt but is an agonist to the MC1RΔ24. We conclude that the deletion in the MC1RΔ24 leads to a receptor with a high basal activity which is further activated by ASIP. This is the first report of ASIP acting as an agonist to MC1R".

Associated gene: